TriangleNCT02312258 · CITED IN SOURCE DOCUMENTS
A Study of Oral Ixazomib Maintenance Therapy in Participants With Newly Diagnosed Multiple Myeloma (NDMM) Not Treated With Stem Cell Transplantation (SCT)
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- COMPLETED
- Registry last update
- 2023-09-21
The purpose of this study is to determine the effect of ixazomib maintenance therapy on progression free survival (PFS) compared with placebo, in participants with NDMM who have had a major response (complete response \[CR\], very good partial response \[VGPR\], or partial response \[PR\]) to initial therapy and who have not undergone SCT.
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What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Progression Free Survival (PFS)
Overall Survival (OS)
Percentage of Participants Who Achieve or Maintain Any Best Response Category During the Treatment Period
Time to Progression (TTP)
Progression Free Survival 2 (PFS2)
Time to Next Line Therapy (TTNT)
Time to End of the Next-line of Therapy After Study Treatment
Duration of Next-line Therapy
Percentage of Participants Who Develop a New Primary Malignancy
Percentage of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative
Correlation of MRD Status With PFS and OS
OS in a High-risk Population
PFS in a High-risk Population
Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) as Measured by the Global Health Status (GHS)
Correlation Between Frailty Status and PFS and OS
Pharmacokinetic Parameter: Plasma Concentration of Ixazomib
Time to Resolution of Peripheral Neuropathy (PN) Events
Time to Improvement of PN Events
Adverse events
Limitations, agreements, and source contact
Who could take part
- eligibility Criteria
- Inclusion Criteria: 1. Adult male or female participants 18 years or older with a confirmed diagnosis of symptomatic newly diagnosed multiple myeloma (NDMM) according to standard criteria. 2. Completed 6 to 12 months (± 2 weeks) of initial therapy, during which the participant was treated to best response, defined as the best response maintained for 2 cycles after the M-protein nadir is reached. 3. Documented major response (PR, VGPR, CR) according to the International Myeloma Working Group (IMWG) uniform response criteria, version 2011, after this initial therapy. 4. Female participants who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, OR * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilized (that is, status postvasectomy), who: * Agree to practice effective barrier contraception during the entire study Treatment period and through 90 days after the last dose of study drug, OR * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception.) 5. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. 6. Complete documentation of the details of the initial therapy before randomization including cytogenetics and International Staging System (ISS) is available. 7. Eastern Cooperative Oncology Group Performance Status of 0 to 2. 8. Suitable venous access for the study-required blood sampling and consent for the specific amounts that will be taken. 9. Is willing and able to adhere to the study visit schedule and other protocol requirements including blood sampling and bone marrow aspiration. 10. Must meet the following clinical laboratory criteria at study entry: * Absolute neutrophil count (ANC) greater than or equal to (≥) 1,000 per cubic millimeter (/mm\^3) without growth factor support and platelet count ≥75,000/mm\^3. Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days before randomization. * Total bilirubin less than or equal to (≤) 1.5\*the upper limit of the normal range (ULN). * Alanine aminotransferase and aspartate aminotransferase ≤ 3\*ULN. * Calculated creatinine clearance ≥ 30 milliliter per minute (mL/min) (using the Cockcroft-Gault equation). Exclusion Criteria: 1. Multiple myeloma that has relapsed after, or was not responsive to, initial therapy. 2. Prior SCT. 3. Radiotherapy within 14 days before randomization. 4. Diagnosed or treated for another malignancy within 5 years before randomization or previous diagnosis with another malignancy. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. 5. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period. 6. Major surgery within 14 days before randomization. 7. Central nervous system involvement. 8. Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before randomization. 9. Diagnosis of Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS), plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome. 10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, uncontrolled congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. 11. Systemic treatment with strong cytochrome P450 3A (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital) or St. John's wort within 14 days before randomization. 12. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection. 13. Comorbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (example, PN that is Grade 1 with pain or Grade 2 or higher of any cause). 14. Psychiatric illness or social situation that would limit compliance with study requirements. 15. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. 16. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment. 17. Treatment with any investigational products within 30 days before randomization.
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- Ixazomib placebo-matching capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 through 26.
- intervention Names
- Drug: Placebo
- label
- Placebo
- type
- PLACEBO_COMPARATOR
- description
- Ixazomib 3 mg, capsule, orally, once on Days 1, 8, and 15 of each 28-day cycle from Cycles 1 to 4 that may have been escalated to 4 mg thereafter up to Cycle 26.
- intervention Names
- Drug: Ixazomib
- label
- Ixazomib
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- Placebo
- description
- Ixazomib placebo-matching capsules.
- name
- Placebo
- type
- DRUG
- arm Group Labels
- Ixazomib
- description
- Ixazomib capsules.
- name
- Ixazomib
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- masking Info
- masking
- QUADRUPLE
- who Masked
- PARTICIPANT
- CARE_PROVIDER
- INVESTIGATOR
- OUTCOMES_ASSESSOR
- primary Purpose
- TREATMENT
Enrollment
- count
- 706
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death from any cause, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. Per IMWG criteria, PD is defined as, increase of 25% of lowest response value in one or more of following criteria: serum M-component (absolute increase ≥0.5 g/ deciliter (dL)); or urine M-component (absolute increase ≥200 mg/24-hour); difference between involved and uninvolved free light chains (FLC) levels (absolute increase \>10 mg/dL); or bone marrow plasma cell percentage (absolute plasma cell percentage ≥10%); development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma; or development of hypercalcemia (corrected serum calcium \>11.5mg/dL).
- measure
- Progression Free Survival (PFS)
- time Frame
- From randomization until PD or death (up to 52 months)
- secondary Outcomes
- description
- OS was measured as the time from the date of randomization to the date of death.
- measure
- Overall Survival (OS)
- time Frame
- From the date of randomization and every 12 weeks after PD on next-line therapy until death (up to 88 months)
- description
- Response was assessed according to IMWG criteria based on IRC assessment. Best response included PR, VGPR and CR. PR= \>=50% reduction of serum M protein and \>=90% or \<200 mg reduction urinary M protein in 24-hour, or \>50% decrease in difference between involved and uninvolved FLC levels, or \>50% reduction in bone marrow plasma cells, if bone marrow plasma cells \>30% and \>50% reduction in size of soft tissue plasmacytomas at baseline. VGPR= \>90% reduction (\<100 mg/24-hour) in serum M-protein + urine M-protein detectable by immunofixation but not on electrophoresis. Complete response= \>5% plasma cells in myelogram with absence of paraprotein in serum and urine according to immunofixation.
- measure
- Percentage of Participants Who Achieve or Maintain Any Best Response Category During the Treatment Period
- time Frame
- Up to 27 months
- description
- TTP is defined as the time from the date of randomization to the date of first documentation of PD, using IMWG criteria.
- measure
- Time to Progression (TTP)
- time Frame
- From randomization until PD or death (up to 52 months)
- description
- PFS2 is defined as the time from the date of randomization to objective PD on next-line treatment using IMWG criteria, or death due to any cause, whichever occurred first.
- measure
- Progression Free Survival 2 (PFS2)
- time Frame
- From the date of randomization to every 12 weeks until second PD or death (up to 88 months)
- description
- TTNT is defined as the time from the date of randomization to the date of the first dose of next-line antineoplastic therapy.
- measure
- Time to Next Line Therapy (TTNT)
- time Frame
- From randomization until PD or death (up to 52 months)
- description
- Time to end of the next line of therapy is defined as the time from the date of randomization to the date of last dose of the next line of antineoplastic therapy following study treatment.
- measure
- Time to End of the Next-line of Therapy After Study Treatment
- time Frame
- From randomization until PD or death (up to 52 months)
- description
- Duration of next-line therapy is defined as the time from the date of the first dose of the next line of antineoplastic therapy coming after study treatment to the date of the last dose.
- measure
- Duration of Next-line Therapy
- time Frame
- From randomization until PD or death (up to 52 months)
- measure
- Percentage of Participants Who Develop a New Primary Malignancy
- time Frame
- From randomization until PD or death (up to 52 months)
- description
- Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry. MRD negativity was defined as absence of MRD and MRD positivity was defined as presence of MRD. MRD was assessed by 8-color flow cytometry with the IMWG recommended sensitivity of 10\^-5.
- measure
- Percentage of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative
- time Frame
- Up to 52 months
- description
- PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurred first, assessed for up to 52 months in this outcome measure. OS was measured as the time from the date of randomization to the date of death, assessed for up to 52 months in this outcome measure. Participants with various types of known MRD status were pooled together for analysis of overall survival in this outcome measure.
- measure
- Correlation of MRD Status With PFS and OS
- time Frame
- From randomization up to 52 months
- description
- High-risk population included but not be limited to participants carrying cytogenetic deletion (del)17, translocation \[t\](4;14), t(14;16). OS was measured as the time from the date of randomization to the date of death.
- measure
- OS in a High-risk Population
- time Frame
- From the date of randomization and every 12 weeks after PD on next-line therapy until death (up to 88 months)
- description
- High-risk population included but not be limited to participants carrying del17, t(4;14), t(14;16). PFS was defined as the time from the date of randomization to the date of first documentation of PD or death from any cause.
- measure
- PFS in a High-risk Population
- time Frame
- From randomization until PD or death (up to 52 months)
Full study description
- brief Summary
- The purpose of this study is to determine the effect of ixazomib maintenance therapy on progression free survival (PFS) compared with placebo, in participants with NDMM who have had a major response (complete response \[CR\], very good partial response \[VGPR\], or partial response \[PR\]) to initial therapy and who have not undergone SCT.
- detailed Description
- The drug being tested in this study is called ixazomib citrate. Ixazomib citrate is being tested to slow progressive disease (PD) and improve overall survival in people who have NDMM who have had a major positive response to initial therapy and have not undergone SCT. This study will look at the effect of ixazomib citrate has on the length of time that participants are free of PD and their overall survival. The study will enrol approximately 700 participants. Participants will be randomly assigned (by chance, like flipping a coin) in 3:2 ratio to Ixazomib or matching placebo groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): * Ixazomib citrate initiates at 3 mg which will be escalated to 4 mg with cycle 5 day 1 * Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient All participants will be asked to take one capsule on Days 1, 8 and 15 of each 28-day cycle. The treatment period will be approximately 24 months (equivalent to 26 cycles) or until patients experience PD or unacceptable toxicities, whichever occurs first. This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 78 to 106 months. Participants will make 28 visits to the clinic during the treatment period and will continue to make follow-up visits every 4 weeks until the next line of therapy begins. Participants will also be contacted by telephone every 12 weeks after last treatment visit for a follow-up assessment.
Source references
- references
- citation
- Paiva B, Manrique I, Dimopoulos MA, Gay F, Min CK, Zweegman S, Spicka I, Teipel R, Mateos MV, Giuliani N, Cavo M, Hopkins CR, Fu W, Suryanarayan K, Vorog A, Li C, Wang B, Estevam J, Labotka R, Dash AB. MRD dynamics during maintenance for improved prognostication of 1280 patients with myeloma in the TOURMALINE-MM3 and -MM4 trials. Blood. 2023 Feb 9;141(6):579-591. doi: 10.1182/blood.2022016782.
- pmid
- 36130300
- type
- DERIVED
- citation
- Dimopoulos MA, Spicka I, Quach H, Oriol A, Hajek R, Garg M, Beksac M, Bringhen S, Katodritou E, Chng WJ, Leleu X, Iida S, Mateos MV, Morgan G, Vorog A, Labotka R, Wang B, Palumbo A, Lonial S; TOURMALINE-MM4 study group. Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial. J Clin Oncol. 2020 Dec 1;38(34):4030-4041. doi: 10.1200/JCO.20.02060. Epub 2020 Oct 6.
- pmid
- 33021870
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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- 5) deaths in the NINLARO arm compared with 26% (69/261) in the placebo arm. The hazard ratio for overall survival was 1.008 (95% CI: 0.744 - 1.367). In C16021 (NCT02312258), newly diagnosed multiple myeloma patients, not treated with a stem cell transplant who achieved a partial response or better, continued on maintenance therap
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Preserved source evidence · Not medical advice